Chemokines, or chemotactic cytokines, are a class of cytokine molecules capable of chemotactically attracting migratory cells. Chemokines are essential in attracting cells to inflammatory sites irrespective of the etiology, including immunologic, infective, ischemic, or drug-induced causes of inflammation. Chemokines generally are small molecular weight molecules in the range of about 8-10 kilodaltons (“kD”).
Most chemokines can be divided into three major families, CC, CXC, and CXXXC, based on the number of amino acids (referred to as “X”) separating the two cysteines (referred to as “C”) in the chemokine molecule. Within the CC and CXC families, chemokines are further grouped into related sub-families based on amino acid sequence similarity. CC chemokine sub-families include the monocyte chemoattractant protein (“MCP”) sub-family and the sub-families that include macrophage inhibitory protein-1α (“MIP-1α”), macrophage inhibitory protein-1β (“MIP-1β”), and the regulated on activation normal T cell expressed (“RANTES”) subfamily. CXC chemokine sub-families include the IP-10 and Mig sub-family, the interleukin-8 (“IL-8”) sub-family, and the PF4 sub-family. The chemokines stromal cell-derived factor 1α (“SDF-1α”) and stromal cell-derived factor 1β (“SDF-1β”) form a chemokine family that is related by amino acid sequence similarity to the both CC and CXC chemokine families.
Chemokines generally exert their effect by binding to chemokine receptors. CC chemokines typically bind to members of the CCR class of receptors, while CXC chemokines typically bind to members of the CXCR class of receptors. These receptors are involved in regulating the extent and nature of inflammation, and certain receptors tend to be localized in certain tissues and cells.
Stromal cell-derived factor-1 (“SDF-1”), a member of the CXC chemokine family, is a potent chemoattractant for hematopoietic cells, including bone marrow progenitors (Aiuti et al., J. Exp. Med., 185:111-120 (1991)), lymphocytes (Bleul et al., Nature (Lond.), 382:828-833 (1996)); monocytes, and polymorphonuclear cells (Bleul et al., J. Exp. Med., 184:1101-1109 (1996)). SDF-1 also stimulates proliferation of β-cell progenitors in vitro (Nagasawa et al., Nature (Lond.), 382:635-638 (1996)). SDF-1 is thus likely to attract hematopoietic cells in appropriate microenvironments in which they differentiate or proliferate in response to local stimuli. SDF-1 is the ligand for CXCR4, a G protein-coupled receptor that is expressed not only in hematopoietic cells but also in a large variety of tissues, such as brain microglia (Lavi et al., Am. J. Pathol., 1035-1042 (1997)), and endothelia (Gupta et al., J. Biol. Chem., 273:4282-4287 (1998)). Accordingly, CXCR4-deficient mice exhibited cardiac defects, abnormal cerebellar development, and anatomical changes of gastrointestinal tract vascularization (Tachibana et al., Nature (Lond.), 393:591-594 (1998)).
SDF-1 is believed to play an important role during embryogenesis and hematopoeisis by recruiting hematopoietic stem cell (“HSC”) precursors to become bone marrow cells. In the adult, SDF-1 is hypothesized to be involved in migration of lymphocytes to lymphoid organs or to sites of inflammation. SDF-1 is expressed in both splenic red pulp and in lymph node medullary cords, as well as on high endothelial venules (“HEV”). Moreover, SDF-1 has been found to induce recruitment of an SDF-1 responsive cell line to human peripheral lymph nodes grafted into SCID mice. However, the entire role of SDF-1 in health and disease is not yet clear.